Project Summary: The main goal of this research is to test the ability of aspirin to prevent estrogen receptor (ER)-negative breast cancer, using a mouse breast cancer model. In particular, we will establish whether aspirin has comparable or greater efficacy than the selective cyclooxygenase 2 (COX-2) inhibitor celecoxib. We and others have previously shown that selective COX-2 inhibitors are protective in rodent breast cancer models. This approach was based on observations of COX-2 overexpression in approximately 40% of human breast cancers, particularly those that are ER-negative and those that overexpress human epidermal growth factor receptor 2, or HER2/neu. However, recent reports of increased cardiovascular risk associated with prolonged use of COX-2 inhibitors diminish the attractiveness of using this class of drugs for cancer chemoprevention. In contrast, the COX inhibitor aspirin is widely used for cardiovascular protection, and has proven effective for preventing colorectal neoplasia. We hypothesize that aspirin may be similarly effective for preventing breast cancer, and may thus provide an alternative to selective COX-2 inhibitors with less attendant risk of adverse cardiac events. As a first test of our hypothesis, we will assay the ability of aspirin to protect against ER-negative breast cancer using MMTV/neu mice. Tumor incidence will be compared in MMTV/neu females administered either aspirin or celecoxib with that in control mice. Secondary endpoints will include: tumor growth rate after initial detection, tumor multiplicity, and frequency of lung metastases. Biological endpoint assays will be performed to investigate the mechanistic basis of observed anti-cancer effects, including assays of mammary prostaglandin levels, proliferation, and apoptosis. Additionally, based on our recent data showing profoundly reduced mammary vasculature in Cox-2 knockout mice, it will be of particular interest to assay drug-mediated effects on mammary angiogenesis. Relevance: Of the 210,000 new breast cancer cases predicted for 2005, one-third will be ER-negative, resulting in an anticipated 12-15,000 deaths. Antiestrogenic approaches offer considerable promise for preventing ER-positive breast cancers, but new approaches are required to prevent ER-negative cancers. This research will test the hypothesis that aspirin can reduce formation of ER-negative breast cancers, using a mouse breast cancer model. Notably, low-dose aspirin has been shown to suppress colorectal tumor formation in a prospective clinical trial. This is particularly important because aspirin-associated gastrointestinal toxicity is thought to diminish with decreasing dose. Thus, a positive result in our proposed study would lay the foundation for future studies of aspirin and breast cancer prevention, and would have important public health implications since aspirin is widely used to protect against cardiovascular disease.